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Evidence base for exercise prehabilitation suggests favourable outcomes for patients undergoing surgery for non-small cell lung cancer despite being of low therapeutic quality: a systematic review and meta-analysis
Department of Clinical Epidemiology, VieCuri Medical Centre, Venlo, the NetherlandsAdelante Rehabilitation Centre, Venlo, the NetherlandsDepartment of Epidemiology, GROW School for Oncology and Reproduction, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands
Department of Clinical Epidemiology, VieCuri Medical Centre, Venlo, the NetherlandsDepartment of Epidemiology, GROW School for Oncology and Reproduction, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the NetherlandsDepartment of Clinical Physical Therapy, VieCuri Medical Centre, Venlo, the Netherlands
Department of Nutrition and Movement Sciences, School for Nutrition and Translational Research in Metabolism (NUTRIM), Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the NetherlandsDepartment of Surgery, School for Nutrition and Translational Research in Metabolism (NUTRIM), Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands
Department of Clinical Epidemiology, VieCuri Medical Centre, Venlo, the NetherlandsDepartment of Epidemiology, GROW School for Oncology and Reproduction, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands
The aim of this systematic review was to evaluate whether exercise prehabilitation programs reduce postoperative complications, postoperative mortality, and length of hospital stay (LoS) in patients undergoing surgery for non-small cell lung cancer (NSCLC), thereby accounting for the quality of the physical exercise program.
Methods
Two reviewers independently selected randomized controlled trials (RCTs) and observational studies and assessed them for methodological quality and therapeutic quality of the exercise prehabilitation program (i-CONTENT tool). Eligible studies included patients with NSCLC performing exercise prehabilitation and reported the occurrence of 90-day postoperative complications, postoperative mortality, and LoS. Meta-analyses were performed and the certainty of the evidence was graded (Grading of Recommendations Assessment, Development and Evaluation (GRADE)) for each outcome.
Results
Sixteen studies, comprising 2,096 patients, were included. Pooled analyses of RCTs and observational studies showed that prehabilitation reduces postoperative pulmonary complications (OR 0.45), postoperative severe complications (OR 0.51), and LoS (mean difference −2.46 days), but not postoperative mortality (OR 1.11). The certainty of evidence was very low to moderate for all outcomes. Risk of ineffectiveness of the prehabilitation program was high in half of the studies due to an inadequate reporting of the dosage of the exercise program, inadequate type and timing of the outcome assessment, and low adherence.
Conclusion
Although risk of ineffectiveness was high for half of the prehabilitation programs and certainty of evidence was very low to moderate, prehabilitation seems to result in a reduction of postoperative pulmonary and severe complications, as well as LoS in patients undergoing surgery for NSCLC.
Surgery versus stereotactic radiotherapy for patients with early-stage non-small cell lung cancer: more data from observational studies and growing clinical equipoise.
Comparison of the outcomes of stereotactic body radiotherapy versus surgical treatment for elderly (>/=70) patients with early-stage non-small cell lung cancer after propensity score matching.
]. In the Netherlands, approximately 35% of all patients with NSCLC who underwent surgery in 2018, developed a postoperative complication, of which 20% within 30 days postoperatively [
Dutch Institute for Clinical Auditing. Jaarrapportage Dutch Lung Cancer Audit 2018. Available from https://dica.nl/jaarrapportage-2018/dlca [accessed 14 September 2022].
Dutch Institute for Clinical Auditing. Jaarrapportage Dutch Lung Cancer Audit 2018. Available from https://dica.nl/jaarrapportage-2018/dlca [accessed 14 September 2022].
]. Especially patients with a high risk for adverse postoperative outcomes might benefit from preoperative interventions such as exercise prehabilitation.
Exercise prehabilitation in patients undergoing lung resection aims to improve a patient's health, including aerobic fitness level in the period between diagnosis and surgery in order to postoperatively reduce the risk for complications and reduce the length of hospital stay (LoS) [
]. Recent systematic reviews in patients with NSCLC reported that exercise prehabilitation may be effective in reducing complications and LoS, but with inconsistent results [
Systematic review and meta-analysis of randomized, controlled trials on preoperative physical exercise interventions in patients with non-small-cell lung cancer.
]. A better assessment of the quality of prehabilitation programs could potentially contribute to the certainty of evidence regarding the merit of prehabilitation to reduce postoperative complications, postoperative mortality, and LoS in patients undergoing surgery for NSCLC. In addition, there are no guidelines concerning the optimal content of an exercise prehabilitation program for preoperatively improving physical fitness to subsequently improve postoperative outcomes in patients with NSCLC. Finally, observational studies are frequently left out of systematic reviews while these studies might actually provide an additional perspective to randomized controlled trials (RCTs) [
Therefore, the aim of this systematic review was to evaluate whether exercise prehabilitation programs reduce postoperative complications, postoperative mortality, and LoS in patients undergoing surgery for NSCLC, thereby accounting for the quality of the physical exercise program. To do so, we employed the international Consensus on Therapeutic Exercise aNd Training (i-CONTENT) tool in this systematic review to help understand, structure, and value the potential of preoperative physical exercises to improve the outcomes of NSCLC surgery [
]. The study protocol was registered at PROSPERO (CRD42021244223). Studies in which postoperative complications, postoperative mortality, and LoS after exercise prehabilitation was compared with usual care or between different frequencies of sessions in prehabilitation programs were selected.
2.1 Literature search
MEDLINE, Embase, and CINAHL databases were searched for eligible studies published up to December 2021. In addition, reference lists from retrieved studies were screened. The search strategy, which has been set up and optimized by the researchers and a librarian, contained a combination of controlled vocabulary (e.g., MeSH or EMTREE) and keyword terms and phrases searched in titles, abstracts, and key word fields, as appropriate. Key terms included in the search strategy are “non-small cell lung cancer” and “lung surgery”, “prehabilitation”, “postoperative complications”, “postoperative mortality”, and “length of hospital stay”. Combinations of text words of the literature search are shown in supplementary file 1.
2.2 Study selection
RCTs and observational studies in patients aged ≥18 years, with ≥95% patients with NSCLC undergoing elective surgery were included. The exercise prehabilitation program could be unimodal or multimodal, but should at least include physical exercise training that aimed to preoperatively improve physical fitness. Usual care groups consisted of patients who either received no intervention (usual care) or a comparison intervention (e.g., a different preoperative physical exercise program). Outcome measures of the studies should at least include postoperative complications, postoperative mortality, and/or LoS. Physical exercise training was defined as a structured form of either aerobic, interval, and/or resistance exercises, based upon validated measurements describing training intensity (e.g., heart rate, rating of perceived exertion, work rate), eventually supplemented with breathing exercises. Studies only involving health promotion initiatives without a structured professional follow-up were excluded in this review. Conference papers, case series, case reports, opinion studies (non-original research), systematic reviews, and studies not published in English were also excluded. Two reviewers (M.V. and R.F.) independently screened titles and abstracts of retrieved records using Rayyan software [
] based on inclusion criteria and exclusion criteria. Thereafter, assessment of full-text articles according to eligibility criteria was performed by the two reviewers (M.V. and R.F.) independently. Any disagreements between reviewers were resolved through discussion and consensus. When no consensus was reached, a third party acted as an adjudicator (M.J.).
2.3 Data extraction
One reviewer (M.V.) extracted data from the included studies by using a standardized extraction form, after which another reviewer (R.F.) checked the extracted data. Extracted data included first author, publication year, number of participants, patient characteristics of the intervention group and control group, disease stage, age (mean; range), sex, type of surgery, and comorbidity. Items of the i-CONTENT tool were also described in terms of content. Characteristics of the physical exercise training program were extracted using the training frequency, training intensity, training time, training type, training volume, and training progression principles (FITT-VP) [
Swain D.P. Guidelines for Exercise Testing and Prescription. ACSM’s resource manual for guidelines for exercise testing and prescription(ninth ed). Wolters Kluwer/Lippincott Williams and Wilkins,
2014: 468-479
] of the prescribed physical exercises of the intervention group and control group. Differences in postoperative pulmonary complications, any complications (Clavien-Dindo grade I-IV), severe complications (Clavien-Dindo grade II-IV), and postoperative mortality (Clavien-Dindo grade V) within 90 days, and LoS between the intervention group and usual care group were evaluated.
2.4 Methodological quality
The two reviewers (M.V. and R.F.) independently assessed the methodological quality of included studies by means of the Cochrane risk of bias tool for randomized controlled trials II (RoB2) [
]. The RoB2 reviews six domains, and the ROBINS-I tool reviews seven domains. In the RoB2 tool, each item was rated as ‘high’, ‘low’, or ‘some’. In the ROBINS-I tool, each item was rated as ‘low’, ‘moderate’, ‘serious’, ‘critical’, or ‘no information’. Risk of bias of the included studies was assessed according to the outcomes postoperative complications, postoperative mortality, and LoS. No global score was given, but the score per study was given based on the relevant outcomes for this systematic review. Discrepancies were resolved by consensus. If no consensus was reached, a third person acted as an adjudicator (M.J.).
2.5 Therapeutic quality
Therapeutic quality of the physical exercise training module of the prehabilitation programs was assessed independently by two reviewers (M.V. and R.F.) using the i-CONTENT tool [
]. Using the i-CONTENT tool, the following eight items were substantively described: 1) patient selection, 2) dosage of the exercise program, 3) type of the exercise program, 4) qualified supervisor, 5) type and timing of outcome assessment, 6) safety of the exercise program, and 7) adherence to the exercise program. To ensure a uniform assessment of the assessors, basic guidelines for the application and interpretation were composed for each item of the i-CONTENT (Table 1) by all authors. The original authors of the i-CONTENT did not provide an aggregated cut-off for which studies could be considered of low, some, or high risk for ineffectiveness. A rating scheme was arbitrarily developed for this study (see supplementary file 2) to determine low and high risk for ineffectiveness per study.
Table 1Basic guidelines for the application and interpretation of therapeutic quality of the physical exercise training module of prehabilitation programs for each item of the i-CONTENT tool [
A VO2peak < 20 mL/kg/min and/or a predicted postoperative VO2peak < 10 mL/kg/min or other selection criteria with clear rationale.
No preselection or selection (described).
2. Dosage of the training program
Intensity and duration of the exercise program must be clearly described and/or based on existing literature relevant to the target population of operable patients with NSCLC and/or an adequate exercise test (e.g., steep ramp test, CPET).
Not described where (the intensity of) the content of the exercise is based on and/or no physiological improvement can be expected due to low training dosage (frequency, intensity, time).
3. Type of the training program
At least aerobic exercise training with or without resistance exercise training.
An intervention inconsistent with the goal of physical exercise training for patients undergoing surgery for lung cancer.
4. Qualified supervisor (if applicable)
Guidance of a physical therapist who is specialized in supervising adult clinical populations.
Supervision is not reported or guidance was provided by a professional other than a physical therapist, or guidance is not described.
5. Type and timing of outcome assessment
-
30- to 90-day follow-up for postoperative complications, length of hospital stay, postoperative mortality.
-
To measure change in preoperative physical fitness, a pre- and post-prehabilitation exercise test must be performed preoperatively, with at least two weeks between the measurements.
Less than 30 days or more than 90 days postoperatively description of follow-up.
6. Safety of the training program
Adverse events related to the exercise program are described and acceptable as would be expected in the studied population.
Adverse events related to the exercise program are higher than would be expected in the studied population.
7. Adherence to the training program
Adherence was determined separately for training frequency and deemed good in case of ≥80%.
Adherence to the training frequency was <80%.
Abbreviations: CPET = cardiopulmonary exercise test, i-CONTENT = international Consensus on Therapeutic Training aNd Training, NSCLC = non-small cell lung cancer, VO2peak = oxygen uptake at peak training.
The effects of prehabilitation versus usual care on postoperative complications, postoperative mortality, and LoS, were analysed using random-effects meta-analysis models. Meta-analyses were performed separately for RCTs and observational studies [
]. For postoperative complications and postoperative mortality, the odds ratios (OR) and 95% CI were calculated using a Mantel-Haenszel model. For LoS, the mean differences (MD) and 95% confidence intervals (CI) were taken from the original studies. Meta-analyses were conducted using Review Manager (version 5.4; Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). A P-value <0.05 was considered statistically significant. Heterogeneity was evaluated using the I2 statistic. Results were classified as follows: 0%–40% indicates low heterogeneity, 30%–60% indicates moderate heterogeneity, 50%–90% indicates substantial heterogeneity, and 75%–100% indicates considerable heterogeneity [
The two reviewers (M.V. and R.F.) independently rated the certainty of evidence for each outcome using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach [
]. In order to interpret the findings, a GRADE summary of findings table was created in which the following outcomes were included: 1) pulmonary complications, 2) any complications, 3) severe complications, 4) postoperative mortality, and 5) LoS. The certainty of evidence was assessed for each outcome by downgrading based on the GRADE criteria for RCTs and upgrading for observational studies. Furthermore, the current systematic review aimed to integrate the overall risk of ineffectiveness scores into the GRADE approach. Within the GRADE approach, risk of ineffectiveness of exercise prehabilitation programs was added under ‘other considerations’. It was devised after consensus between the researchers that if at least 80% of the studies for a certain outcome measure had an overall risk of ineffectiveness of low or some, the GRADE level of certainty was upgraded by one level.
3. Results
3.1 Study characteristics
A total of 1,299 records were identified with the systematic search. After removing duplicates, 1,052 unique records were screened on title and abstract after which 47 full text articles were reviewed. Reasons for exclusion are described in Supplementary file 3. After full-text review, sixteen studies were included, of which twelve randomized controlled trials (RCTs) [
Impact of one-week preoperative physical training on clinical outcomes of surgical lung cancer patients with limited lung function: a randomized trial.
Two-week multimodal prehabilitation program improves perioperative functional capability in patients undergoing thoracoscopic lobectomy for lung cancer: a randomized controlled trial.
]. The studies included a total of 2,094 patients with operable NSCLC with pathological stage I, II, III, or IV. The sample size of the studies ranged from 19 to 939 patients, with a mean age-range between 56.2 and 74.4 years. Surgical procedures in the studies consisted of video-assisted thoracic surgery (n = 9), open thoracotomy (n = 5), lobectomy (n = 2), robot-assisted thoracic surgery (n = 2), pneumonectomy or bilobectomy (n = 1), pneumonectomy (n = 1), and segmentectomy (n = 1). Fifteen studies compared exercise prehabilitation with usual care [
Impact of one-week preoperative physical training on clinical outcomes of surgical lung cancer patients with limited lung function: a randomized trial.
Two-week multimodal prehabilitation program improves perioperative functional capability in patients undergoing thoracoscopic lobectomy for lung cancer: a randomized controlled trial.
] compared ≥3 prehabilitation sessions per week with <3 prehabilitation sessions per week. Postoperative complications and LoS were reported in all studies [
Impact of one-week preoperative physical training on clinical outcomes of surgical lung cancer patients with limited lung function: a randomized trial.
Two-week multimodal prehabilitation program improves perioperative functional capability in patients undergoing thoracoscopic lobectomy for lung cancer: a randomized controlled trial.
Impact of one-week preoperative physical training on clinical outcomes of surgical lung cancer patients with limited lung function: a randomized trial.
Two-week multimodal prehabilitation program improves perioperative functional capability in patients undergoing thoracoscopic lobectomy for lung cancer: a randomized controlled trial.
Impact of one-week preoperative physical training on clinical outcomes of surgical lung cancer patients with limited lung function: a randomized trial.
Two-week multimodal prehabilitation program improves perioperative functional capability in patients undergoing thoracoscopic lobectomy for lung cancer: a randomized controlled trial.
Impact of one-week preoperative physical training on clinical outcomes of surgical lung cancer patients with limited lung function: a randomized trial.
Two-week multimodal prehabilitation program improves perioperative functional capability in patients undergoing thoracoscopic lobectomy for lung cancer: a randomized controlled trial.
6: ASA grade III, 4: stage IV, 5: neoadjuvant therapy, 2: declined to participate, 2: contraindications for 6 MWT distance, 1: severe renal insufficiency
Prehab: 2 referred to preoperative physical therapy, 2: not evaluated, 1: reconversion to thoracotomy, 1: not surgery, 1: not malignant disease. UC: 2: not malignant disease, 1: neoadjuvant therapy, 2 abandoned intervention, 2: surgery re-scheduled, 1 irresectable tumour, 1 excluded by the investigators, 1: other
Prehab: 70.9 ± 6.1 UC: 69.0 ± 4.4, p = NR
‐
Colinet comorbidity score: Prehab: mean 9.3 ± 4.3, UC: mean 8.7 ± 4.2, p = NR
Impact of one-week preoperative physical training on clinical outcomes of surgical lung cancer patients with limited lung function: a randomized trial.
Two-week multimodal prehabilitation program improves perioperative functional capability in patients undergoing thoracoscopic lobectomy for lung cancer: a randomized controlled trial.
Two-week multimodal prehabilitation program improves perioperative functional capability in patients undergoing thoracoscopic lobectomy for lung cancer: a randomized controlled trial.
Impact of one-week preoperative physical training on clinical outcomes of surgical lung cancer patients with limited lung function: a randomized trial.
Two-week multimodal prehabilitation program improves perioperative functional capability in patients undergoing thoracoscopic lobectomy for lung cancer: a randomized controlled trial.
Impact of one-week preoperative physical training on clinical outcomes of surgical lung cancer patients with limited lung function: a randomized trial.
Two-week multimodal prehabilitation program improves perioperative functional capability in patients undergoing thoracoscopic lobectomy for lung cancer: a randomized controlled trial.
] (50%) of tidal volume training. Duration of prehabilitation programs varied between one and four weeks, with a training frequency between one and seven times per week. Training session duration (time) varied between 15 and 120 min per session. The exact content of the prehabilitation programs is reported in Table 3.
Table 3Content of exercise prehabilitation according to the items of therapeutic quality on the i-CONTENT tool.
First author, year
Patient selection Eligible if:
Type and dosage of the preoperative exercise program (F: Frequency, I: intensity, T: Time, T: Type)
Including a low, moderate, or high-risk group was interpreted according to the patient selection in the included studies and the score on the i-CONTENT tool.
: Moderate to severe COPD and FEV1 <80%
‐
Based on: NR
‐
Program duration: 1 week
‐
Aerobic exercises:
F: 2/day, I: NR, T: 20 min, T: treadmill or cross-trainer (Nu-Step) and arm-R-size exercises or arm-ergometer Resistance exercises: F: 2/day, I: at least light intensity on the Borg scale, T: 2 × 10–12 repetitions, T: Thera band Breathing exercises: F: 1/day, I: perceived exertion of somewhat hard on the Borg scale, T: 15–20 repetitions, T: Threshold Inspiratory Muscle Trainer or P-Flex valve
Including a low, moderate, or high-risk group was interpreted according to the patient selection in the included studies and the score on the i-CONTENT tool.
Including a low, moderate, or high-risk group was interpreted according to the patient selection in the included studies and the score on the i-CONTENT tool.
: Age >70 years, BMI >30, COPD with heavy smoking history (≥20 pack-years) FEV1 ≤70%, or prior thoracic surgery
Including a low, moderate, or high-risk group was interpreted according to the patient selection in the included studies and the score on the i-CONTENT tool.
Including a low, moderate, or high-risk group was interpreted according to the patient selection in the included studies and the score on the i-CONTENT tool.
: >75 years and >20 pack-year smoking history and BMI >30 kg/m2 and ppoFEV1 <60% and ppoDLCO <60% and COPD
Impact of one-week preoperative physical training on clinical outcomes of surgical lung cancer patients with limited lung function: a randomized trial.
Including a low, moderate, or high-risk group was interpreted according to the patient selection in the included studies and the score on the i-CONTENT tool.
Including a low, moderate, or high-risk group was interpreted according to the patient selection in the included studies and the score on the i-CONTENT tool.
F: 2–3/week, I: 80–100% of peak work-rate near-maximal heart rates toward the end of each series of sprints based on the individual's exercise response, T: 2 series of 10 min with 15-sec work-interval and 15 s rest-interval with 4-min rest between series, T: cycling Resistance training: F: 2–3/week, I: NR, T: NR, T: leg press, leg extension, back extension, seat row, biceps curls, or chest and shoulder press
Two-week multimodal prehabilitation program improves perioperative functional capability in patients undergoing thoracoscopic lobectomy for lung cancer: a randomized controlled trial.
Including a low, moderate, or high-risk group was interpreted according to the patient selection in the included studies and the score on the i-CONTENT tool.
F: 3/week, I: based on Borg-score 13–16 and 70% of heart rate reserve, T: 30 min, T: jogging or walking or cycling Resistance exercises: F: 2/week, I: Borg-score moderate to high (13–16), T: 3 x 3–12 repetitions, T: major muscle groups with Thera band Breathing exercises: F: 2/day, I: NR, T: 10 min, T: 1) A Tri-Ball Respiratory Training (Leventon S.A., Barcelona, Spain) for breathing exercises; 2) cough exercises; 3) blowing up a small balloon in 1 breath and holding for >5 s
Home-based, instruction and resistance exercises supported by a physical therapist
‐
30-day postoperative complications
‐
30-day postoperative mortality
‐
LoS
‐
Safety: no adverse events
‐
Dropouts: Prehab: 2 (6%) did not receive surgery, UC: 2 (6%) did not receive surgery
Including a low, moderate, or high-risk group was interpreted according to the patient selection in the included studies and the score on the i-CONTENT tool.
: Previous pulmonary disease, interstitial lung disease, COPD with impaired spirometry function
‐
Based on: NR
‐
Program duration: 4 weeks
‐
Aerobic exercises:
F: 5/week, I: 80% on the maximum work rate achieved during a treadmill incremental test, T: 10 min in the first week with increments of 10 min every week, T: walking on a treadmill Breathing exercises: F: 1/day, I: 20% on the maximal inspiratory pressure (MIP), increased 5–10% each session, to reach 60% of their MIP, T: 10–30 min, T: Threshold Inspiratory Muscle Trainer
Including a low, moderate, or high-risk group was interpreted according to the patient selection in the included studies and the score on the i-CONTENT tool.
: ASA I-II
‐
Based on: NR
‐
Program duration: 1 week
‐
Aerobic exercises:
F: 3/day, I: according to patient's tolerance to training speed and time, T: NR, T: walking on a treadmill
Including a low, moderate, or high-risk group was interpreted according to the patient selection in the included studies and the score on the i-CONTENT tool.
Including a low, moderate, or high-risk group was interpreted according to the patient selection in the included studies and the score on the i-CONTENT tool.
Including a low, moderate, or high-risk group was interpreted according to the patient selection in the included studies and the score on the i-CONTENT tool.
Including a low, moderate, or high-risk group was interpreted according to the patient selection in the included studies and the score on the i-CONTENT tool.
: FEV1 ⩽80%, BMI ⩾30; (c) age ⩾75 years or two or more co-morbidities identified in the Colinet Comorbidity Score.
F: 3–5/week, I: interval training (1 min at high intensity (80% of WRpeak) plus 4 min of active rest (performed at 50% of WRpeak) measured with the CPET, T: 30 min, T: cycling Resistance exercises: F: 3–5/week, I: 25 repetition maximum test, T: 3 × 15 repetitions, T: six training using Thera band and body mass for the large muscle groups Breathing exercises: F: 2/day, I: 80% of vital capacity, T: 6 cycles of 5 repetitions, T: incentive spirometry coach2
Physical therapist
‐
90-day postoperative complications
‐
LoS
‐
Safety: no adverse events
‐
Dropouts: Prehab: 2 (17%): lost to follow up, UC: 1 (10%): clinical deterioration
Including a low, moderate, or high-risk group was interpreted according to the patient selection in the included studies and the score on the i-CONTENT tool.
PUREAIR protocol: randomized controlled trial of intensive pulmonary rehabilitation versus standard care in patients undergoing surgical resection for lung cancer.
Including a low, moderate, or high-risk group was interpreted according to the patient selection in the included studies and the score on the i-CONTENT tool.
: ≥50 years and ≥20 pack-year smoking history and BMI ≥28 kg/m2 and FEV1 ≤60% and COPD, asthma or airway hyper reactivity
‐
Based on: NR
‐
Program duration: 1 week
‐
Aerobic exercises:
F: 1/day. I: according to own speed and power, then increasing progressively, T: 30 min, T: cross-trainer (Nu-Step) Breathing exercises: F: 2–3/day: I: NR, T: 15–20 min, T: Volume training: abdominal breathing and inspiratory training with the Voldyne 2500
Education and teaching supported by a nursed specialized in lung cancer, aerobic exercise supervised by a physical therapist
‐
30-day postoperative complications
‐
30-day postoperative mortality
‐
Safety: NR
‐
Dropouts: Prehab:
7
(19%): required for advancing the surgery, 9 (24%): perceived lack of benefit, 11 (30%): could not endure the high-intensive regimen, 7 (19%): considered time/expense cost and suspended, 3 (8%): other reasons
‐
Exercise adherence: NR
Abbreviations: 1RM = one repetition maximum, BMI = body mass index, COPD = chronic obstructive pulmonary disease, CPET = cardiopulmonary exercise test, DLCO = carbon monoxide lung diffusion capacity, ECOG = Eastern cooperative oncology group, FEV1 = forced expiratory volume in 1 s, i-CONTENT = international Consensus on Therapeutic Training aNd Training, min = minute, LoS = length of hospital stay, NR = not reported, ppoDLCO = predicted postoperative carbon monoxide lung diffusion capacity, ppoFEV1 = predicted postoperative forced expiratory volume in 1 s, Prehab = prehabilitation group, UC = usual care group, VO2peak = oxygen uptake at peak training, WRpeak = work rate at peak exercise.
a Including a low, moderate, or high-risk group was interpreted according to the patient selection in the included studies and the score on the i-CONTENT tool.
Impact of one-week preoperative physical training on clinical outcomes of surgical lung cancer patients with limited lung function: a randomized trial.
Two-week multimodal prehabilitation program improves perioperative functional capability in patients undergoing thoracoscopic lobectomy for lung cancer: a randomized controlled trial.
] had a high risk of bias. High risk of bias was mainly caused by an unclear description of the randomization process (n = 5), unclear assignment to intended interventions (n = 6), and poor adherence to intended interventions (n = 7). Of the four included observational studies, two [
] a serious risk of bias. The latter was mainly caused by a high risk on the items confounding (n = 2), patient selection (n = 2), and a poor description of the intervention classification (n = 1).
Table 4Results of methodological quality according to the Cochrane risk of bias tool and the Robins-1 tool, and therapeutic quality according to the i-CONTENT tool.
Table 4Results of methodological quality according to the Cochrane risk of bias tool and the Robins-1 tool, and therapeutic quality according to the i-CONTENT tool.
3.4 Therapeutic quality of the exercise prehabilitation programs
Assessment of the risk of ineffectiveness based on the content of the exercise prehabilitation programs is described in Table 4. One physical exercise training program [
Two-week multimodal prehabilitation program improves perioperative functional capability in patients undergoing thoracoscopic lobectomy for lung cancer: a randomized controlled trial.
Impact of one-week preoperative physical training on clinical outcomes of surgical lung cancer patients with limited lung function: a randomized trial.
] (50%) had a high risk of ineffectiveness. Main factors that increased the risk of ineffectiveness of exercise prehabilitation programs were inadequate patient selection (n = 10), inadequate dosage of the physical exercise training program (n = 10), inadequate description of type and timing of the outcome assessment (n = 6), and low adherence to the physical exercise training program (n = 5).
3.5 Effects of prehabilitation on postoperative complications, length of hospital stay, and postoperative mortality
3.5.1 Postoperative pulmonary complications
Postoperative pulmonary complications were assessed in eight RCTs [
Impact of one-week preoperative physical training on clinical outcomes of surgical lung cancer patients with limited lung function: a randomized trial.
] (Fig. 1A). The pooled result of these studies showed a statistically significant lower incidence of postoperative pulmonary complications in the prehabilitation groups compared to the usual care groups in RCTs (OR 0.31, 95% CI 0.20 to 0.48; I2 0%) and observational studies (OR 0.60, 95% CI 0.41 to 0.88; I2 0%). Certainty of the evidence according to the GRADE approach was moderate and very low for RCTs and observational studies, respectively (see Table 5). The one observational study [
] which compared a different number of prehabilitation session with each other was not included in the meta-analysis reported that ≥3 prehabilitation sessions per week significantly reduced postoperative pulmonary complications compared to performing <3 sessions a week (p < 0.01).
Fig. 1The effect of exercise prehabilitation compared to usual care on postoperative pulmonary complications (A), any postoperative complications (B), any postoperative severe complications (C) postoperative mortality (D), and length of hospital stay (E).
Fig. 1The effect of exercise prehabilitation compared to usual care on postoperative pulmonary complications (A), any postoperative complications (B), any postoperative severe complications (C) postoperative mortality (D), and length of hospital stay (E).
Impact of one-week preoperative physical training on clinical outcomes of surgical lung cancer patients with limited lung function: a randomized trial.
Two-week multimodal prehabilitation program improves perioperative functional capability in patients undergoing thoracoscopic lobectomy for lung cancer: a randomized controlled trial.
] (Fig. 1B). The meta-analysis showed that the incidence of any complications was significantly lower in patients receiving prehabilitation compared to patients receiving usual care (OR 0.44, 95% CI 0.30 to 0.64; I2 42%). The GRADE certainty of evidence was low based on RCTs and very low based on observational studies (see Table 5).
Impact of one-week preoperative physical training on clinical outcomes of surgical lung cancer patients with limited lung function: a randomized trial.
Two-week multimodal prehabilitation program improves perioperative functional capability in patients undergoing thoracoscopic lobectomy for lung cancer: a randomized controlled trial.
] separately assessed severe complications (Fig. 1C). The pooled results showed that prehabilitation significantly reduced the risk of severe complications in RCTs (OR 0.36, 95% CI 0.20 to 0.68; I2 0%) and observational studies (OR 0.56, 95% CI 0.29 to 1.06; I2 32%). The GRADE certainty of evidence was moderate based on RCTs and low based on observational studies (see Table 5).
3.5.4 Postoperative mortality
The effect of prehabilitation on postoperative mortality was assessed in six RCTs [
Impact of one-week preoperative physical training on clinical outcomes of surgical lung cancer patients with limited lung function: a randomized trial.
Two-week multimodal prehabilitation program improves perioperative functional capability in patients undergoing thoracoscopic lobectomy for lung cancer: a randomized controlled trial.
] (Fig. 1D). The effect of prehabilitation on postoperative mortality was not significant in both the RCTs and observational studies (RR 0.63, 95% CI 0.14 to 2.83; I2 0% and RR 1.88, 95% CI 0.44 to 8.05; I2 0%) with a very low certainty of evidence according to GRADE (see Table 5).
] (Fig. 1E). LoS was shorter in the prehabilitation groups compared to usual care in RCTs (mean difference (MD) −3.02 days, 95% CI −4.82 to −1.22; I2 85%) with a very low certainty according to the GRADE approach (see Table 5). In observational studies, no significant differences were found between prehabilitation and usual care (MD -0.60 days, 95% CI -3.95 to 2.75; I2 54%) with a very low certainty according to the GRADE approach. The one study that was not included in the meta-analysis [
] found a significant reduction (3.5 days) of LoS in the group that performed ≥3 prehabilitation sessions a week compared to the prehabilitation group that performed <3 sessions a week.
4. Discussion
The aim of this systematic review was to evaluate whether exercise prehabilitation programs reduce postoperative complications, postoperative mortality and LoS in patients undergoing surgery for NSCLC, thereby accounting for the quality of the physical exercise programs. The pooled estimates of the RCTs show that prehabilitation results in a reduction of postoperative pulmonary complications, severe postoperative complications, and postoperative LoS. Pooled estimates of the included observational studies also indicate that exercise prehabilitation may reduce postoperative complications and LoS. However, the GRADE certainty of evidence of each outcome was very low to moderate.
Results of the current review are in line with previous research, as several systematic reviews have shown that exercise prehabilitation might be an effective intervention for reducing postoperative complications and LoS in NSCLC/lung resection [
Systematic review and meta-analysis of randomized, controlled trials on preoperative physical exercise interventions in patients with non-small-cell lung cancer.
], the certainty of evidence was described. However, the certainty of evidence was described without an explanation to which content it was assessed on, which is a major limitation. Nevertheless, previous reviews neither described nor assessed the quality of the content of the physical exercise training module of included prehabilitation studies. Although prehabilitation seems effective, it remains unclear how an optimally effective exercise prehabilitation program should be designed.
The finding that prehabilitation improved most postoperative outcomes, despite the fact that half of the included studies in this systematic review had a high risk of ineffectiveness, might suggest that the full potential of prehabilitation might not have been unlocked. Main concerns with regard to the risk of ineffectiveness were that most included studies (63%) did not specially select patients with a higher risk for postoperative complications and even seemed to exclude them [
Impact of one-week preoperative physical training on clinical outcomes of surgical lung cancer patients with limited lung function: a randomized trial.
Two-week multimodal prehabilitation program improves perioperative functional capability in patients undergoing thoracoscopic lobectomy for lung cancer: a randomized controlled trial.
Associations between pretreatment physical performance tests and treatment complications in patients with non-small cell lung cancer: a systematic review.
Associations between pretreatment nutritional assessments and treatment complications in patients with stage I-III non-small cell lung cancer: a systematic review.
Impact of one-week preoperative physical training on clinical outcomes of surgical lung cancer patients with limited lung function: a randomized trial.
]. Full reporting of the prescription and adherence to of exercise prehabilitation is eminent for adequate estimation of the risk of ineffectiveness, and thereby the quality of the exercise program. Merely three studies offered a personalized physical exercise prescription based on outcomes of the cardiopulmonary exercise test of any other formal exercise test [
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